IE61661B1 - Phenoxy-substituted beta-carboline derivatives, their production and their use as drugs - Google Patents
Phenoxy-substituted beta-carboline derivatives, their production and their use as drugsInfo
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- IE61661B1 IE61661B1 IE299686A IE299686A IE61661B1 IE 61661 B1 IE61661 B1 IE 61661B1 IE 299686 A IE299686 A IE 299686A IE 299686 A IE299686 A IE 299686A IE 61661 B1 IE61661 B1 IE 61661B1
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- carboline
- methoxymethyl
- chlorophenoxy
- carboxylic acid
- ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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Abstract
Phenoxy-substituted beta-carbolines of the formula I (I) X is COOR3, CONHC1-3-alkyl or oxadiazolyl of the formula R2 is H, lower alkyl or cycloalkyl, R3 is lower alkyl, R4 is hydrogen, lower alkyl or lower alkoxyalkyl, R1 is hydrogen, halogen, lower alkyl, lower alkoxy, acyl, phenyl, C2-5 alkylenedioxy, trifluoromethyl, nitrilo, nitro, lower alkoxycarbonyl, azido, SO2R6, SO2NR7R8, or NR9R10, R6 is lower alkyl, R7 and R8 independently are lower alkyl or together with the nitrogen atom form a hetero ring, R9 and R10 independently are hydrogen, lower alkyl, acyl or together with the nitrogen atom form a hetero ring system, with the proviso that X is not COOEt, if (a) is 5-phenoxy and R4 is methyl or (b) is 6-(4-methoxyphenoxy) and R4 is methoxymethyl have valuable pharmacological properties.
Description
The invention relates to novel phenoxy-substituted β-carboXine * derivatives, to their preparation and to their use as medicaments.
£P-A~130 140,, which contains 6-(4-methoxyphenoxy)-4methoxymethyl-fi-carboline-3-carboxylic acid ethyl ester, and SP-A-54507, which contains 5-phenoxy-4-methyl-B-carboline-3carboxylic acid ethyl ester, describe compounds that have the action on the central nervous system known of β-earbolines.
The compounds according to the invention have the general formula I JS wherein is an oxadiazolyl radical of the formula wherein Rz is H, Chalky! or C3„7cycloalkyl, or is a COOR3 group wherein R3 is Ci.§alkyl, or is CONHCi.3alkyl, and is hydrogen, C._6alkyl or Ci„salkoxyalkyl and B1 is hydrogen, halogen, Cj.6alkyl, C.^alkoxy, Ci.*alkanoyl, phenylf C2.3alkylenedioxy, trifluoromethyl, cyano, nitro, C^alkoxycarbonyl, azido, 5O2R% SO2NR'R® or NR’r10, R6 is C^alkyl, ?/ and R® are Chalky! or together with the nitrogen atom form a saturated 5- or 6-membered heterocycle in which one or two CH2 groups may have been replaced by oxygen, sulphur or nitrogen, and Fr and Rw are each hydrogen, Ci_6alkyl, Ci.«alkanoyl or together 10 with the nitrogen atom form a saturated 5- or 6-membered heterocycle in which one or two CH2 groups may have been replaced by oxygen, sulphur or nitrogen, and there being from or different, and wherein X is -phenoxy and R" to 3 substituents R1, which may be identical not COOC2H3 when R1— is methyl or when pA θ-0-is ΖΣΛ-ο-is -(4-methoxyphenoxy) and R" is methoxymethyl.
The novel β-carboline derivatives of the general formula I can be mono- or di-substituted in the A-ring in positions 5-8, with substitution in the 5- or 6- position being preferred.
There may be one or more, preferably from 1 to 3, identical or different substituents Rl on the aryl radical.
Lower alkyl is to be understood as being straight-chain or branched-chain radicals having from 1 to 6 carbon atoms. The preferred Cj.-alkyl radicals may be mentioned by way of example, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert.-butyl and sec.-butyl.
The eycloalkyl radical R2 aay contain from 3 to 7 carbon atoms, with radicals having from 3 to 5 carbon atoms being preferred, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl etc..
The acyl radical is derived preferably from aliphatic carboxylic acids having up to 4 carbon atoms, such as, for example, formic acid, acetic acid, propionic acid, butyric acid etc..
When R7R8 and r’r10 together with the nitrogen atom form a heterocycle, that heterocycle is 5- or 6-membered and saturated, it being possible for one or two CH2 groups to have been replaced by oxygen, sulphur or nitrogen.
The following radicals may be mentioned by way of example: imidasolidinyl, pyrasolidinyl, piperidinyl, pyrrolidinyl, piperasinyl, morpholinyl, thiomorpholinyl, isothiasolidinyl etc..
Halogen is to be understood as being fluorine, chlorine, bromine and iodine.
Surprisingly the compounds according to the invention exhibit psychotropic properties that are superior to those of the above-mentioned B-carbolines in pharmacological tests, as can be seen from the Table by way of the example of some of the compounds according to the invention.
The compounds according to the invention exhibit especially anxiolytic and anticonvulsive activity. in order to investigate the anticonvulsive action, the relief of spasms induced by pentylenetetrasole (pentasole) has -been investigated. Pentasole is administered subcutaneously in an amount of 150 mg/kg as a hydrochloric acid solution (pH 2-3) & to 30 minutes after the intraperitoneal administration of the test substance. That amount induces clonic and tonic spasms which result in the death of untreated animals. The number of mice exhibiting spasms and the number thereof which have died 30 minutes after the pentazole is recorded (PTZ spasm antagonism).
The ED50 values shown in the Table are determined in accordance with the method of Litchfield and Wilcoxon, (J. Pharmacol, exp.
Ther. 9? (1949) 99-103) as the amount of antagonistically active substance that protects 50 % of the animals from spasms and death. -phenoxy ch3 cooc2h5 5-(2-Cl-phenoxy) ch2och3 0 — »\t 5-(2-Cl-phenoxy) ck2och3 -COOCH(CH3)2 5-(2,4-dichlorophenoxy) ch2och3 -cooc2hs 6-(2-nitrophenoxy) ch2och3 -COOCK(CH3)2 6-(2-cyano-3-Cl-phenoxy} ch2och3 -COOCH(CH3)2 6-(2-cy*nophenoxy) ch2och3 -COOCH(CH3)2 6-(4-acetylphenoxy) ch2ock3 5-phenoxy ch2och3 -CQOSfc 5-phenoxy ch2och3 ¢2- AZ 5- phenoxy 6- phenoxy ch3 ch3 Ai O— A/ —0 U x' /v —κ (- ICsoEBS0 PTZ (ng/ml) (mg/kg) (ED§q) in vitro in vivo mg/kg in vivo 2.0 s 30 3,1 11 0.8 2,6 19 4 2.9 3.2 4 0.33 1.0 13 0.67 3,01 0.29 3.0 < 0.43 7.7 0.3 0.3 0,4 10 0.6 0.3 0.1 4.3 3,9 2 3.2 2.6 2.4 1' « It is known that certain sites in the central nervous system of vertebrates exhibit a high specific affinity for the binding of 1,..4- and 1,5-benzodiazepines (Squires, «1. F. and Braestrup, C., Nature (London) 266 (1977) 734). Those sites are called benzodiazepine receptors.
The pharmacological properties of th© compounds according to the invention have been determined by examination of their ability to displace radioactively-labelled flunitrazepam from benzodiazepine receptors.
The displacement activity of the compounds according to the invention is given in the form of IC50 and SD50 values. The IC50 value indicates the concentration that brings about a 50% displacement of the specific binding of H3-flunitrazepam (1.0 ηϊί, 0°C) in samples with a total volume of 0.55 ml of a suspension of brain membranes, e.g. of rats.
Th© displacement test is performed as followss 0.5 ml of a suspension of untreated, rat forebrain in 25 mM KK2PO4, pH=7.1 (5-10 mg of tissue/sample) is incubated for 4060 minutes at 0°C together with 3H-diazepam (specific activity 14.4 Ci/mmol, 1.9 nM) or 3K-flunitrazepam (specific activity 87 Ci/mmol, 1.0 nM). After incubation, the suspension is filtered through a fritted glass filter, the residue is washed twice with cold buffer solution and the radioactivity is measured on a scintillation counter.
The test is than repeated, but prior to the addition of the radioactively-labelled benzodiazepine there is added a specific amount or an excess amount of the compound the displacement activity of which is to be determined. The IC50 value can then be calculated on the basis of the values obtained.
The ED50 value rspresenxs the dose of a test substance that brings about a reduction in the specific binding of the £ lunitrazepam to the benzodiazepine receptor in a living brain to 50% of the control value.
The in vivo test is performed as follows: Groups of mice are injected with the test substance in different doses and normally intraperitoneally. After 15 ainutes the 3H-flunitrazepam is administered intravenously to the mice. After another 20 minutes the mice are sacrificed., their forebrain is removed and the radioactivity specifically bound to the brain membranes is measured by scintillation counting. The ED50 is determined from the dose/activity curves.
The novel compounds of the general formula I have valuable pharmacological properties. In particular they act on the central nervous system and are thus suitable as psychotropic drugs in human medicine, and they are used especially for the treatment of anxiety accompanied by depressions, epilepsy,, sleep disturbances, spasticities and muscle relaxation during anaesthesia. The compounds according to the invention have also been found to have amnestic or memory-promoting properties.
The compounds according to the invention can be used for the formulation of pharmaceutical preparations , for example for oral and parenteral administration to humans,, according to galenic methods known osr se.
Suitable auxiliaries for the formulation of pharmaceutical preparations are those physiologically compatible organic and inorganic carriers for enteral and parenteral administration that are inert towards the compounds according to the invention.
Carriers that may be mentioned are, for example, water, salt solutions „ alcohols,» polyethylene glycols g polyhydroxyethoxy lated castor oil, gelatins, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilised and/or may be mixed with auxiliaries, such as lubricants, preservatives, stabilisers, wetting agents, emulsifiers, buffers and dyes.
Especially suitable for parenteral administration are injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil.
For oral administration there are suitable especially tablets, dragfies or capsules with talc and/or a hydrocarbon carrier or binder, such as, for example, lactose, corn starch or potato starch. Administration can take place also in liquid form, for example as a syrup to which a sweetening agent may be added.
The compounds according to the invention are incorporated in a dosage unit of 0.05 to 100 mg of active substance in a physiologically compatible carrier.
The compounds according to the invention are administered in a dose of 0.1 to 300 mg/day, preferably 1-30 mg/day.
The compounds ox the general formula I according to the invention are prepared according to methods known oer ss, For example, the compound ox the general formula X is prepared by - 10 I-' fooaula IE (II) wherein Rl and R'* have the meanings ·, given i above with a compound of the formula «3 R* ___c 1 wherein R* has the meaning given above, to fora a compound of the general formula ϊ wherein X. is the radical wherein R3 has the meaning given above. fe) reacting a compound of the general formula III ij#L <2 (XI wherein R* and R* have the meanings given above, with a carboxylic acid anhydride (R*CO)2O wherein Rl has the meaning given above, to form a compound ef the general formula I wherein X is the radical —P -a2 wherein Rj has the meaning given above, c) reacting a compound of the general formula IV compound, of the formula with a Hal· wherein R1 . has the meaning given above and R' is an electrophilic substituent, and optionally then cs) a nitro group is reduced to the amino group and, if desired., the resulting amino group is deaminated or replaced by halogen or azide, or J5) when R1 is halogen, is catalytically dehalogenated, or y) an ester group is transesterified or hydrolysed and, if desired, the resulting carboxylic acid is amidated.
Hal represents halogen, preferably fluorine and. chlorine.
Por the introduction of the l,2,4-oxadiasol=5yl radical, the 15 β-carboline-carboxylic acid of the general formula II is condensed with an amidoxime of ths formula R2-C(^OS)Sn2, in an inert solvent that boils above 100°C and is inert towards the reactant, at the reflux temperature of the reaction mixture. Suitable solvents for the condensation reaction are, for example, toluene and dimethylformamide. Advantageously, the free β-carboline-3-carboxylie acid is activated in a suitable manner before the condensation reaction. For this purpose, the free acid can be converted, for example, into the mixed anhydride, into the activated ester or into the chloride» Activation to the imidasolide has also proved successful with imidazole/thionyl chloride or also carbonyl diimidazole in an aprotic solvent such as dioxane, tetrahydrofuran, dimethyl formamide or N-methylpyrrolidone at temperatures between 0° and 50°C, preferably room temperature.
For the introduction of the 1,2,4-oxadiazol-3-yl radical, for example, the 3-carboxylic acid nitrile is reacted with hydroxylamine to form a compound of the general formula XIX. The B-carboline-3-carboxamidoxime thus obtained is mixed with the acid anhydride (R2CO)2O at room temperature and then heated to boiling temperature. The reaction is complete after about 7 hours and work-up is carried out in accordance with the usual method.
I The introduction of the phenoxy radical takes place preferably by reaction of a compound of the general formula XV with a fluorobenzene derivative, which advantageously carries a further electrophilic substituent.
As electrophilic substituents R1’ there may be mentioned, for example, the following radicals listed for Rxs nitro, lower alkoxycarbonyl, lower alkylsulphonyl, trifluoromethyl, cyano, etc. .
The reaction with the substituted halobenzene derivative is performed in a basic medium in dipolar aprotic solvents at temperatures up to the boiling point of the solvent.
Suitable solvents are, for example, dimethylformamide, dimethyl sulphoxide, dimethylacetamide, N-methyIpyrrolidinone, hexamethyl-phosphoric acid triamide. etc..
Suitable bases include alkali metal compounds such as, for example, sodium or potassium hydroxide, sodium or potassium carbonate etc., optionally also in the presence of phase transfer catalysts, such as, for example, crown ethers such as 18-crown-S., dicyclohexyl-18-crovn~S, dibenso-18-crown-S or Aliquat 336.
The operation is advantageously performed under an inert gas atmosphere, for example under nitrogen or argon.
The reduction of the nitro group to the amino group is effected, for example, catalytically in polar solvents at room temperature.
Preferably, palladium on a support such as carbon, or platinum in finely divided form is used as catalyst; in the case of compounds containing halogen, Raney nickel is preferably used as catalyst.
All inert solvents are suitable for the reduction, such as, for example, alcohols or ethers such as methanol, ethanol, diethyl ether, tetrahydrofuran or mixtures thereof, etc..
Hydrogenation can be performed under normal pressure or H2 pressure.
The deamination is effected, for example, according to the Sandmeyer process known in the literature. In that case the diazonium compound produced intermediately with a nitrite is boiled down reductively at elevated temperature in the presence of copper(I) oxide and hypophosphorous acid.
The introduction of the halogens chlorine, bromine or iodine via the amino group can, for example, also fake place according to Sandmeyer by reacting the diazonium salts, formed intermediately with nitrites, with copper(I) chloride or copper(I) bromide in the presence of the corresponding acid, hydrochloric acid or hydrobromic acid, or with potassium iodide.
The introduction of fluorine is effected, for example, by the Balz-Schiemann reaction of diazonium tetrafluoroborate.
The introduction of the azido group is effected by the Sandmeyer reaction of the diazonium salt with alkali metal azide, for example.
The catalytic dehalogenation is performed, for example, with palladium on carbon (10%) with the addition of organic bases, for example triethylamine, etc., in alcohols.
In order to avoid transesterification it is advantageous to use the alcohol of the ester component as solvent.
If transesterification is desired, it is possible to carry out the reaction, for example, with the corresponding alcohol or alkali metal alcoholate; optionally, titanium tetraisopropylate can be added in anhydrous alcohol as catalyst. The transesterification is usually performed at temperatures of S0-12Q°C and is complete after about 2-6 hours.
The introduction of th® tert.-butyl aster group is effected, for example, by reaction of the carboxylic acid with tert. -butoxy-bis-dimethylaminomethane. The reaction is generally performed under an inert gas atmosphere such as argon or nitrogen and with the exclusion of moisture at elevated temperature.
The hydrolysis of the ester group can thus take place in an acidic or alkaline manner? preferably It is hydrolysed in an alkaline manner by heating the ester to temperatures up to the reflux temperature of the reaction mixture with dilute agueous alkali, such as potassium or sodium hydroxide, in a protic solvent, such as, for example, methanol, ethanol or ethylene glycol.
Carboxylic acid amides are obtained, for example, by reaction with amines from the corresponding imidazolides which are produced intermediately from the carboxylic acids and carbonyl diimidizole or thionyl diimidazole. The reaction is performed at room temperature in dipolar aprotic solvents, such as, for example, dimethylformamide, dimethylacetamide, etc..
The production of the starting compounds is known or is effected according to known processes, as described, for example, in EP-A-130 140.
For example, the esters can be produced by activation of the corresponding acid and subsequent reaction with the desired alcohol.
The following Examples are intended to illustrate ths process according to the invention.
Example ,1 - (4-£Jb,l a^flMifiihyXxfircaxteQlIflS .74g of 5-(4~chlorophenoxy)-4-methoxymethyl-0~carboline-3car.boxy lie acid are dissolved in 150 ml of absolute dimethylformamide; 2.91 g of carbonyl diimidazole are added and the mixture is stirred for 3 hours at room temperature. To this solution there are added 3.9S g of propionamidoxims, and the mixture is stirred for 8 hours, a further 1 g of propionamidoxime is added and the mixture Is again stirred for 8 hours. After concentration by evaporation under an oil pump vacuum, the mixture Is taken up in toluene and refluxed for 8 hours. After concentration by evaporation, the mixture is chromatographed twice over silica gel, first with methylene chloride/ethanol = 13:1 and then with hexanes- acetone = 1:1 as eluant. After recrystallisation from ethyl acetate/hexane and drying over phosphorus pentoxide at 80eC in vacuo, 2.2 g of -(4-chlorophenoxy-3-(3-ethyl-l,2, 4-oxadiazol~5~yl)-4methoxymethyl-fl-carboline having a melting point of 170°C are obtained.
There are produced in analogous matters -phenoxy-4-methyl-3~(3-ethyl-1,2, 4-oxadiazol-5-yl)-βcarboline, melting point 245-248°C; -(4-nitrophenoxy) - 3-( 3-ethyl-1,2 ,, 4-oxadiazol-5-yl) -βcarboline, melting point 290°C; - ( 4-chlorophenoxy) -4-methyl-3- (3-ethyl-1,2,4-oxadiazol-S-yl) β-carboline, melting point 193-194°C; 6- ( 4-acetylphenoxy) -4-methoxymethyl-3- ( 3-ethyl-l, 2,4oxadiazol-5~yl)-β-carboline, melting point 213-21S°C; - (4-nitrophenoxy) -4-methyl-3- (3-ethyl-l, 2,4-oxadiazol-5-yl) β-carboline, melting point 287°C; - (4-nitrophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2,4-oxadiazol5-yl)-β-carboline melting point 125-180°G; - phenoxy-4-methoxymethyl-3- ( 3-ethyl-1,2 e 4-oxadiasol-S-yl) -β carboline, melting point 168-171°C; 6- phenoxy-3-(3-ethyl-l,2,4-oxadiasol-5-yl)-B-carboline melting point 205-208oC; 6-phenoxy-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β carboline, melting point 247-250°C; 6- ( 4 - nit rophenoxy) - 3-- ( 3-ethy 1-1,2,4 -oxadiazol-5-yl) - β carboline, melting point 288-294°C; 6-(4-aminophenoxy)-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β 10 carboline, melting point 207-210°C; 6-( 4-chlorophenoxy) -4-methyl-3- (3-ethyl-l, 2,4-oxadiazol-5-yl) β-carboline, melting point 245-250°C; 6-(4-nitrophenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl) 3-ce.rboline, melting point 250-258°C; 6-(4-aminophenoxy)-4-methyl-3~(3-ethyl-l,2,4~oxadiazol~5~yl) B-carboline, melting point 245-255°C; ' 6-( 4-chiorophenoxy) - 4-methoxymethyl-3 - ( 3-ethyl-l, 2,4 oxadiasol-5-yl)-B-carboline, melting point 178-192°C; 6- (4-chlorophenoxy)-4-methoxymethyl-3- (3-cyclopropyl-l,, 2,4 oxadiazol-5-yl)-β-carboline, melting point 192-193°C? 6- (4-bromophenoxy) -4-methojqnaethyl-3- (3-ethyl-l, 2,4-oxadiazol - yl)-β-carboline, melting point >280°C; 6- phenoxy-4-met hoxymethyl-3-(3-ethyl-l,2,4-oxadiasol-5-yl)-β carboline, melting point 164°C? - (4-nit rophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2,4-oxadiazol - yl)-B-carboline, melting point 223-225°C; 6- (4-nitrophenoxy) -4-methoxymethyl-3-(3-cyclopropyl-l, 2, & oxadiazol-5-yl)-B-carboline, melting point 22S°C; 6- (2-nitrophenoxy) -4 -methoxymethyl-3- (3-ethyl-l, 2,4-oxadiazol 30 5-yl)-β-carboline, melting point 206-211°C; 6-( 2-nitrophenoxy) -4-methoxymethyl-3-(3-cyclopropyl-l, 2,4 oxadiasol~5~yl)-B-carboline, melting point 154-155°C; 6-( 4-aminophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2,4-oxadiazol -yl)-B-carboline,melting point 249-255°C; 6-(2-methyl-4-nitrophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4 oxadiasol-5-yl)-B-carboline, melting point 208-209°C1? 6-( 4-xnorpholinosulphamoylphenoxy) -4-aethoxyntethyl-3~ (3-ethyl1.2.4- oxadiazol~5-yl)-β-carboline,» melting point 113°C; 6- ( 4~morpholinosulphamoylphenoxy)-4-methoxymethyl-3~(3cyclopropyl-1,2,4-oxadiasol-5~yl)-β-carboline, melting point 139-140°Cj 6- (4~diethylsulphamoylphenoxy) -4-methoxymethyl-3- (3-ethyl1.2.4- oxadiazol-5-yl)-β-carboline, melting point 184-189°C; 6-( 4 -methyl sulphonylphenoxy) -4-methoxymethyl-3- (3-ethyl-l,2,4oxadiazol-5-yl)-β-carboline, melting point 150°C; 6-(4-ethoxycarbonylphenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4oxadiasol-5-yl)-β-carboline, melting point 185-191°Ct 6- ( 2-chlorophsnoxy) -4-methoxymethyl-3- ( 3-ethyl-l, 2,4oxadiazol-5-yl)-β-carboline, melting point 158-161°C? 6- (4-cyanophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2,4-oxadiazol5- yl)-β-carboline, melting point 224~225OC? S (2-chloro-4»nitrophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2 ,.4oxadiazol-5-yl)-β-carboline, melting point 200-213°C; 6- (2-chloro-4-aminophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2, 4oxadiazol~5-yl)-β-carboline, melting point 235-247°C: 6-(2,4-dichlorophenoxy) -4-methoxymethyl-3-(3-ethyl-l,2,4oxadiazol-5-yl)-β-carboline, melting point 1SO~174°C 6- ( 4-f luorophenoxy) -4-methoxymethyl-3- ( 3-ethyl-l ,2,4oxadiazol-5-yl)-β-carboline, melting point 240-242°C; - ( 3-chlorophemoxy) -4~methoxymethyl-3~ ( 3-ethyl-l ,2,4oxadiazol-5-yl)-β-carboline, melting point 170-172°C.
Exafflole_2. 4-Methpxymethyl-5-phenoxv-3- (3-( 5-ethvl-l, 2,4-oxadlazol) -vl) fir£arholine 7 mmol of 4-methoxymethyl~5-phenoxy~fl-carboline-3carboxamidoxime and 1 ml of propionic acid anhydride are stirred for 2 hours at 20°G and then for 5 hours at 120°C After concentration, 10 ml of tetrahydrofuran are added, and the reaction mixture is allowed to stand overnight, then concentrated in vacuo and the reaction product is extracted as an oily substance with 30 ml methylene chloride.
The starting material is produced as follows : (a) 5-Phenojr/jA-^me tho.x3gaetJiylcfic.carboXtne-3-caxbdxamida 2.7 g of 5-phenoxy-4-methoxymethyl-fl-carboline-3carboxylic acid are added to a solution of 30 mmol ox thionyl diimidasole in 150 ml of tetrahydrofuran. The reaction mixture is stirred in for 5 hours and filtered. 12 ml of 25% NH3 in water are added to the filtrate, and the mixture is stirred overnight and concentrated to 50 ml in vacuo After the addition of 100 ml of water, 2 g of the desired product are obtained as yellow crystals. (b) 5cPhenoxy-3-cyanp-4-methQxymethyl-fl-carboJLXne 1.1 g of Br2 in 10 ml of methylene chloride are added dropwise at 0°C to a stirred solution of 1.8 g (15 mmol) of triphenylphosphine in 50 ml of methylene chloride. Then, 2 g of 5-phenoxy-4~methoxymethyl-fl-carboline-3carboxamide and 1.9 ml of triethylamine are added. The reaction mixture is stirred for 1 hour at 0°C and then stirred vigorously with 25 ml of methylene chloride and 25 ml of water for 5 minutes. After removal of the aqueous phase, 0.8 g of the desired product is obtained from the organic phase by concentration. (c) 4r:Methoxym^laicl5 -phehoyzTfl~carbol ine- 3 -carboxamido^yne A mixture of 329 mg (0.001 mol) of 3-cyano-4-methoxymethyl-5-phenoxy~B-carboline, 100 mg of hydroxylamine hydrochloride, 20 ml of ethanol (99%) and 0.52 ml of a % aqueous potassium carbonate solution is refluxed for hours. The reaction mixture is filtered and the filtrate concentrated. 10 ml of water are added to the resides, and the crystalline solid is filtered off and washed with water.
Isaasifi-J.
-(^-Nitroohenoxvl-4rJie-thQxyraethyl-B-carboline-3-carhox-ylic acid ethyl ester .5 g of anhydrous potassium carbonate are added to 6 g of 5hydroxy-4-methoxymethyl β-carboline-3-carboxylic acid ethyl ester under nitrogen, in 200 ml of dimethyl formamide and the mixture is stirred for 1 hour at room temperature.
After the addition of 2.8 g of 4-fluoronitrobensene the mixture is heated for 2 hours at a bath temperature of 100°C. After a further addition of 1.4 g of 4-£luoronitrobenzene, the mixture is heated at !00°C for a further 45 minutes. After cooling, the mixture is poured onto ice and suctioned off. The filter cake is chromatographed, over silica gel with acetoneshexane = 1.1 as eluant. 5.7 g (70% of theory) of 5(4 -nitrophenoxy) -4-methoxymethyΙ-β-c arhol ine- 3 -c arboxy 1 ic acid ethyl ester having a melting point of 231~232°C are obtained.
There are produced in analogous manner: -(2-nitrophenoxy)-4-methyl-fl-carboline-3-carboxylic acid ethyl ester, melting point 241~242°C: -(2-nitrophenoxy)-4-ethyl-B-carboline-3-carboxylic acid ethyl ester? - 3- (4-cyanophenoxy) -4-methoxymethyl -B-csrboline-3-carboxylic acid ethyl ester, melting point 226-227°C? 6- (2 -nitrophenoxy )-4 -methoxymethyl -β-carbo 1 ine- 3 -c arboxy 1 ic acid isopropyl ester, melting point 147-150°C? 6- (2-formyIphenoxy) -4-methoxymethyl-B-carboline"3-carboxylic acid isopropyl ester; melting point 188-192°C; 6-(2-cyanophenoxy)"4-methoxymethyl-B~carboline~3-carboxylic acid isopropyl ester; melting point 170°C; 6-( 2-cyano-3-chlorophenoxy) -4-methoxymethyl-B~carboline-3~ carboxylic acid isopropyl ester, melting point 117-125°C? 6-( 2-acetylphenoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 112-117°C; - (.2 -cyano-4 - fluorophenoxy) -4 -methoxymethyl-B-carboline-3carboxylic acid isopropyl ester, melting point 228-2 30°C? 6- ( 4-acetylphenoxy) -4-methoxymethyl-B"Carboline-3-carboxylic acid isopropyl ester, melting point 233°C; - (4-nitrophenoxy) -4~methyl-B-carboline-3-carboxylic acid ethyl ester, melting point 225°C; - (4-nitrophenoxy) ~4-ethyl-B-carfooline-3-carboxylic acid ethyl ester, melting point 217-218°C? -(4-nitrophenoxy)-B-carboline-3-carboxylic acid ethyl ester, melting point >242°C; - (4-nitro-2-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylie acid ethyl ester, - (4-nitro-3-methylphenoxy) -4-methoxymethyl~B-carboline-3carboxylic acid ethyl ester, melting point 212-213OC; -( 4-nitro-2-methy Iphenoxy) -4-methoxymethyl-B-carboline-3" carboxylic acid ethyl ester, melting point 190-192°C; - (4-ethoxycarbonylphenoxy) »4-methoxymethyl-B~carboline-3carboxylic acid ethyl ester, melting point 157°C; 6- (4-nitrophenoxy)-B-carboline-3-carboxylic acid methyl ester; 6-(4-nitrophenoxy)-B~carfooline-3~carboxylic acid ethyl ester, melting point >250°C; 6-( 4-nitrophenoxy) -4-methyl-fl-carboline-3-carboxylic acid ethyl ester, melting point 288-292oC; 6-(4-nitrophenoxy)-4-methoxymethyl-'B-carboline~3-carboxylic acid ethyl ester, melting point 231-232°C; 6-(2-cyano-3-chlorophenoxy) -4-methyl-B~carboline~3-carboxylic acid isopropyl ester, melting point 230~232°C; 6-( 2-cyano-5-£luorophenoxy) -4»methoxymethyl-B-carboline-3~ carboxylic acid isopropyl ester, melting point 175°C? 6-( 2-cyano-3-f luorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester, melting point 208°C? 6- (2-isopropoxycarbonylphenoxy) -4-methoxymethyl-B-carboline3-carboxylic acid Isopropyl ester, melting point 1<5°C? 6-( 2-tert. -butoxycarbonylphenoxy) -4-raethoxymethyl~B-carboline~ 3-carboxylic acid isopropyl ester, melting point 136°C? 6-( 4-f luoro-2-nitrophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? 6-( 4-nitro-3-chlorophenoxy) -4-methoxymethyl-B-carboline~3carboxylie acid isopropyl ester? 6- (4-nitro-3-methylphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? 6-( 2-nitro-3~chlorophenoxy) -4»methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? 6-( 2-nitro-3,5-dichlorophenoxy) -4-methoxymethyl-B-carboline3-carboxylic acid isopropyl ester? 6-(2-nitrophenoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester, melting point I53-155°C? 6-( 4-nitro~3-methoxyphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point X92-203°C? 6-( 4-nitro-2-methylphenoxy) -4-methoxymethyl~B~carboline-3carboxylie acid ethyl ester, melting point 184-185°C? 6-( 4-nitro-2-chlorophenoxy)-4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 1S5°C? 6-(4-nitro-3-methylphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, malting point 183-184°C? 6-( 2-nitro-4~tri£luoromethylphenoxy) -4-methoxymethyl-Bcar.boline-3-carboxylic acid ethyl ester, melting point 90°C? - (4-ethoxycarbonylphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 181°C? 6- (4-trif luoromethy Iphenoxy) -4~methoxyraethyl~B~carboline~3carboxylic acid ethyl ester, melting point 226-227°C? 6-( 4-methyl sulphony Iphenoxy) -4-mathoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 204-205°C? - (4-f or my lphenoxy) -4-methoxymethyl-B-carboline-3~carboxylic acid ethyl ester, melting point 190-X92°C? -( 2-nitro-4-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester,» melting point 160-162°C? - ( 2-nitro-5-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 155-170°C? 6- (4-nitro-2-methylphenoxy) ~4-m3thoxymethyl-B-carboline~3~ carboxylic acid isopropyl ester? (2-nitrophenoxy)~4-ethyl-B~carboline-3-carboxylicacid ethyl ester? β- (2-nitro-4 -me thoxyphenoxy) -4-methoxymethyl-B~carboline-3carboxyiic acid isopropyl ester? 6-( 4-nitro-3-methoxyphenoxy) -4-methoxymethyl-B-carboline-3 carboxylic acid isopropyl ester? 6- (4-nitro-3-cyanophenoxy) -4-methoxymethyl-B-carboline-3~ carboxylic acid isopropyl ester? 6-( 2-nitro-4-methylphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? 6-(2-methoxy-4-nitrophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? 6- (4-morpholinosulphamoylphenoxy) -4-methoxymethyl-B-carboline3-carboxylic acid ethyl ester, melting point 100°C (decomp.)? 6-( i-diethylsulphamoylphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 1/9°C? 6-(2-ethylsulphonylphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 196-198°C? Example 4 - (4 -Aminoohenoxv) - 4 -methoxvme t hvl^B-carbo 1 ine- 3 -carboxyl ic acid ethvi ester g of 5-(4-nitrophenoxy)-4-methoxyraethyl-B-carboline-3carboxylic acid ethyl ester are hydrogenated in 450 ml of methanols tetrahydrofuran ~ 1:1 with 7.5 g of palladium on carbon (10%) at room temperature under hydrogen normal pressure. After filtration and concentration, the reaction mixture is recrystallised from ethanol, and 10.8 c (77% of theory) of 5-(4-aminophenoxy)-4~methoxy-methyl-B-carboline-3" carboxylic acid ethyl ester having & melting point of 222224°C are obtained.
There are produced in analogous manners -(4-aminophenoxy)-4-methyl-B-carboline-3-carboxylie acid ethyl ester, melting point 170-172°C? - (4-aminophenoxy) -4-ethyl-B-carholine-3-carboxylic acid ethyl ester, melting point 235°C? 6- (4-aminophenoxy)-4-methyl"B-carboline-3~carboxylic acid ethyl ester? 6-(4-aminophenoxy)-4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester, melting point 204-234°C? 6-( 4-amino-3-chlorophenoxy) -4-methoxymethyl-B~carbolin©-3carboxylic acid, isopropyl ester? 6- (4-amino-3~msthylphenoxy) -4~methoxymethyl-B-carboline-3" carboxylic acid isopropyl ester; 6- ( 2-amino-3-chlorophenoxy) "4-methoxymethyl-B-carboline~3~ carboxylic acid isopropyl ester? 6- (2-amino-3,5-dichlorophenoxy) -4-methoxymethyl-B-carboline3-carboxylic acid isopropyl ester? - (2-amino-5~chlorophenoxy) -4-methoxymethyl~B~carboline-3~ carboxylic acid ethyl ester? 6- (4-amino-2-methylphenoxy) -4-methoxymethyl-B~carboline-3~ carboxylic acid isopropyl ester? 6- (4-f luoro-2-aminophenoxy) -4-methoxymethyl-B-carboline-3carboxylie acid isopropyl ester? 6- (4-amino-2-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? S~(2-amino-4-methoxyphenoxy)-4~methoxymethyl~B-carboline-3" carboxylic acid isopropyl ester? 6-(4-amino-3 -methoxyphenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester? 6-(4-amino-3-cyanophenoxy)-4-methoxy»ethyl-fl-carboline-3carboxylie acid isopropyl ester; 6- ( 2-am ino-4-me thyl phenoxy) -4-methoxymethyl-fl-carboline-3carboxylic acid isopropyl ester; 6~(2-methoxy-4-aminophenoxy)-4-methoxymethyl-fl-carboline~3carboxylic acid isopropyl ester; -(4-aminophenoxy)-4-methoxymethyl-fi-carboline-3-carboxylic acid isopropyl ester; melting point >250°C.
In a fundamentally analogous but using Raney nickel as catalyst and the tetrahydrofuran as solvent there are produced: - (4-amino-3-chlor ophenoxy) -4~methoxymethyl-B-carboline-3carboxylic acid ethyl ester, melting point 202-204°C; - (4-amino-2-chlorophenoxy) ~4-methoxymethyl~fi-carfooline-3carboxylic acid ethyl ester, melting point 204°C; 6- ( 4-amino-2-chlorophenoxy) -4-methoxymethyl-fl-carboline~3carboxylic acid ethyl ester, melting point 95-106°C.
Example 5 -Phenoxy-4-mQthoxymethyl-fi-carboline-3-carboxylic acid ethyl ester, 978 mg of 5-( 4-aminophenoxy)-4~methoxymethyl-B-carboline-3carboxylic acid ethyl ester are suspended in 2 ml of water and 10 ml of a 50% tetrafluoroboric acid. After cooling to 0°C, a solution of 224 mg of sodium nitrate in 2 ml of water is added dropwise thereto and the mixture is stirred at 0°C for 1/2 hour. Then, at the same temperature, 4 ml of a 60% hypophosphorous acid and 150 mg of copper (I) oxide are added and the mixture is diluted with 10 ml of water and afterwards heated for 1/2 hour on a steam bath. After adjustment of the pH to 8 with sodium carbonate and the addition of ammonia,, the mixture is extracted with ethyl acetate. The ethyl acetate phase is concentrated by evaporation and the residue is chromatographed over silica gel with acetone: hexane = lxl as eluant. 540 mg (57% of theory) of 5-phenoxy-4-methoxy-methylB-carboline-3-carboxylic acid ethyl ester having a melting point of 174-17S°C are obtained.
There are produced in analogous manners -phenoxy-B-carboline-3-casboxylic acid ethyl ester, melting point 246°C; - (3-chlorophenoxy) -4-methoxymethyl-B-carboline-3~carboxylic acid ethyl ester, melting point 194-197°C; - (2-chlorophenoxy) -4-methoxymethyl-B-carboline-3"Carboxylic acid ethyl ester, melting point 175-177°C; - phenoxy-B-carboline-3-carboxylic acid ethyl ester, melting point 241-242°C; 6- phenoxy-4-methyi-B-carboline-3-carboxylic acid ethyl ester; 6-phenoxy-4~methoxymethyl-B-carboline-3-carboxylic acid ethyl ester; melting point 172-174°C; 6-( 3-chiorophenoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 164°C; 6-( 3-methylphenoxy ) -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 170-174°C; 6-(3,5-dichlorophenoxv)-4-methoxymethyl-B-carboline-3carboxylie acid isopropyl ester, melting point 210°C; 6-( 2-methylphenoxy) =4-methoxymethyl-B"carboline-3~carboxylic acid isopropyl ester, melting point 165~170°C; - ( 2-5-dichlorophenoxy)-4-methoxymathyl~B-carboline-3carboxylie acid ethyl ester, melting point 194-196°C; □ (4-methoxyphenoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester; 6- ( 3-cyanophenoxy) - 4-methoxymet.hyl-B-carbolins-3-carboxylic acid isopropyl ester; 6- (3-methoxyphenoxy) -A-methoxymethyl-B-carboline-S-carboxylic acid isopropyl ester; β- (4 -methy Iphenoxy) ~4-methoxymethyl~B-carboline-3-carboxylic acid isopropyl ester; 6-(2-me tho xyphenoxy) -4~methoxymethyl-B-carboline-3~carboxylic acid isopropyl ester.
Example & - f 4-Chlorophenoxy) -4-methoxymethyJ-B2^garbg_li-ne^3-carbaxylic acid ethyl ester 195 mg of 5-(4-aminophenoxy)-4-methoxymethyl-B-carboline-3carboxylic acid ethyl ester are suspended in a mixture of 2 ml of water and 2 ml of concentrated hydrochloric acid and, after cooling to 0°Ct. a solution of 35 mg of sodium nitrite in 0.5 ml of water is added dropwise thereto. After the addition is complete, the mixture is stirred for 45 minutes at 0°C, a bright yellow solution being formed. To that solution there is added dropwise at 0°C a solution prepared beforehand by adding 69 mg of sodium sulphite in 0.5 ml of water to 250 mg of copper(II) sulphate .5HZO and 87 mg of sodium chloride in 1 ml of water, suctioning off the precipitate and dissolving in 0.5 ml of concentrated hydrochloric acid. After the addition is complete, a yellow precipitate has appeared and the mixture is then heated on a steam bath until the evolution of gas has ceased. The mixture is then diluted with water, rendered alkaline with ammonia solution and extracted with ethyl acetate. After concentration of the organic phase by evaporation it is chromatographed over silica gel with methylene chlorides- ethanol = 10si as eluant. 130 mg (55% of theory) of 5-(4-chlorophenoxy) -4~methoxymethyl-B-carboline-3~ carboxylic acid ethyl ester having a melting point of 207°C are obtaineds There are produced in analogous manners -(4-chlorophenoxy)-4-methyl-B-carboline-3-carboxylic acid ethyl ester? - ( 2,4-dichlorophenoxy)~4-methoxymechyl-fi~carboline-3carboxylic acid ethyl ester, melting point 156-158°C? 6- (4 -chlorophenoxy) -4-methyl-fl-c arbo 1 ine- 3 -c arboxy 1 ic acid ethyl ester, melting point 176-188°C; 6-( 4-chlorophenoxy) -4-methoxymethyl-e-carboline-3-carboxylic acid ethyl ester, melting point 178°C? 6-(2,4-dichlorophenoxy)-4-methoxymethyl-β-carboline-3» carboxylic acid ethyl ester? ~ (4-iodophenoxy) -4-methoxymethyl-fl-carboline»3-carboxylic acid ethyl ester, melting point 200°Cj 6- (2-bromophenoxy) -4-methoxymathyl-fl-carboline-3-carboxylic acid isopropyl ester, melting point 152-X60°C? a-(4-fluoro-2-c hlorophenoxy)-4-methoxymethyl-β-c arboline-3carboxylic acid isopropyl ester, melting point 134-l44°Cj 6-(2,3-dichlorophenoxy)-4~methoxyffiethyl-B-earboline~3carboxylic acid isopropyl ester, melting point 100-101°C? 6-(4-piperidinoazophenoxy)-4"methoxymsthyl-fl-carboline-3carboxylic acid isopropyl ester, melting point 168-174°C? 6-(4-bromophenoxy) -4-methoxymethyl-fi-carboline-3~carboxylic acid ethyl ester, melting point 169-175°C? 6-(4-azidophenoxy) -4-methoxymethyl-fl-carboline-3~carboxylic acid ethyl ester, melting point 169-175°C. 5Phenoxy-4-methoxvmethyl-fi-car.boline-3."Carboxvl.ic acitLXsopEOpyl^. ester .540 mg of 5-phenoxy-4-methoxymethyl-B-3-carboxylic acid ethyl ester in 30 ml of isopropanol are refluxed for 2 hours with 0.2 ml of titanium(IV) isopropylate. After concentration, Q.5N hydrochloric acid is added and the mixture Is extracted with ethyl acetate. The ethyl acetate phase is dried, filtered and concentrated and digested with diisopropyl ether. 450 mg (82% of theory) of 5-phenoxy-4~methoxymethyl-B29 filtered and concentrated and digested with diisopropyl ether. 450 mg (82% of theory) of 5-phenoxy-<-methoxymethyl-βcarboline-3-carboxylic acid Isopropyl ester having a melting point of 207-209°C are obtained.
There are produced in analogous manner: -phenoxy-4-methyl-β-carboIine-3-c arboxy1ic acid isopropy1 ester; -(4-chlorophenoxy)-4-methyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 266-2S8°C; - (4-chlorophenoxy) -4~methoxymethyl-B~carboline~3--carboxylic acid isopropyl ester, melting point 215-218°C; -(4-nitrophenoxy)-4-methyl-fl-carboline-3-carboxylic acid isopropyl ester, melting point 262°C; - (4-nitrophenoxy) -4-methoxymethyl-fi-carboline-3-carboxylic acid isopropyl ester, melting point 207-209°C; 6"phenoxy~4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 181°C; o- (4-chlorophenoxy) -4-methoxymethyl-B~carboline-3-carboxylic acid isopropyl ester, melting point 178-181°; 6-( 4-cyanophenoxy) -4~methoxymethyl-fl-carboline-3-carboxylic acid isopropyl ester, melting point 226-227°C; 6- (2-chlorophenoxy) -4-methoxymethyl~fi-carboline-3-carboxylic acid isopropyl ester, melting point 103-109°C; 6- (4-isopropoxycarbonylphenoxy) -4~methoxymethyl~fi-carboline25 3-carboxylic acid isopropyl ester, melting point 167°C; 6-( 3-chloro-4-nitrophenoxy) -4-methoxymethyl-fi~carboline-3carboxylic acid isopropyl ester, melting point 105-115°C; 6-(2,4-dichlorophenoxy)-4-methoxymethyl-fl-carboline-3carboxylie acid isopropyl ester, melting point 75-78°C; S-(4-fluorophenoxy) -4-methoxymethyl~B-carboline-3-carboxylic acid isopropyl ester, melting point 104-116°C; - (3-chlorophenoxy) -4-raethoxymethyl~B~carboline-3-carboxylie acid Isopropyl ester, melting point 187-189°C; 6-(3,4-dichlorophenoxy)~4-methoxymethyl-B-carboline-3carboxylie acid isopropyl ester, melting point 6S-68°C. !j-Phenoxv-4-metho^naethvl-fl-carbolj,:ne-3-carboyi£lic_acrid i-sopropyl^stex 2g of 5- (4-chlorophenoxy) ~4~methoxymethyl-B"Carboline"3carboxylic acid isopropyl ester in 40 sal of isopropanol are hydrogenated with 200 mg of palladium on carbon (10%) and 0.9 ml of triethylamine at room temperature under normal hydrogen pressure. After filtering off the catalyst, concentrating the filtrate and digesting the residue with diisopropyl ether, 1.4 g of 5-phenoxy-4*-methoxymethyl-e-carboline-3-carboxylic acid isopropyl ester having a melting point of 201~203°C are obtained.
Example 9 -ghenoxv~4-methoyvmethyl-fl-carbol_ine~3~carboxvlic acidtert. butyl ,es„tea 300 mg of 5~phenoxy-4~methoxymethyl-fi-carboline-3"carboxylic acid are heated at 120°C with 2 ml of animal ester for 3 hours, a solution being formed. After dilution with water the mixture is extracted with ethyl acetate. The organic phase is dried, filtered, concentrated and chromatographed over silica gel with acetone:hexane = 1:1 as eluant. 130 mg of 5-phenoxy4-methoxymethyl~B-carholine-3~carboxylic acid tert.-butyl ester having a decomposition point of 150°C are obtained.
There are produced in analogous manners 6-(2-cyanopheno3«y)~"~methoxymethyl-B-carfooline-3-earboxylic acid tert.-butyl ester, melting point 144°C? — (2-cyano~3-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid tert.-butyl ester, melting point 100°C? 6-(2,3-dichlorophenoxy)~4~methoxymethyl~B-carboline~3carboxylie acid tert.-butyl ester, melting point 203-204°G? 6-( 4-fluorophenoxy) -4-n»ethoxymethyl-B-carboline-3-carboxylic acid tert.-butyl ester, melting point 189-191°C? - (4-nitrophenoxy)~4-methoxymethyl-B-carboline-3-cartaoxylic acid tert.-butyl ester, melting point 221-222°C? 6- (4~chlorophenoxy)-4-methyl-B-carboline-3-carhoxylic acid tert.-butyl ester? 6-phenoxy-4~methoxymethyl'-B-carboline-3-carboxylic acid tert. butyl ester. -(4 -Chlor opheno xv) - 4 -methoxvmethyl -β-c arbo 1 ine- 3 -c arboxv1 ic ajcid^ isopropylamide 382 mg of 5-(4-chlorophenoxy)-4-methoxymefhyl-B~carboline-3" carboxylic acid in 10 ml of dimethyl formamide are mixed with 380 mg of carbonyl diimidasole. After 2 hours' stirring at room temperature, 1 ml of isopropylamine is added and the mixture is stirred overnight. After the addition of water the mixture is extracted with ethyl acetate. The ethyl acetate is dried, filtered and concentrated. The residue is chromatographed over silica gel with methylene chlorides acetone = lsl as eluant. 90 mg of 5-(4-chlorophenoxy)-4methoxy-methyl-B-carboline-3-carboxylic acid isopropylamide having a melting point of 255°C are obtained.
There are produced in analogous manners -phenoxy-4-methoxymethvl-B-carboline-3-c arfooxy1ic There are produced in analogous manners -phenoxy-4-methoxymethyl-B-carboline"3-carboxylic acid methylaraide, melting point 235°C; - (4-chlorophenoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid methylamide, melting point 23S°C? - (4-nitrophenoxy)-4-methoxymethyl-B -carbo1ine-3-carboxylic acid isopropylamide? 6- phenoxy-4-msthoxymethyl-B-carboline-3-carboxylic ac id isopropylamide ? 6-( 4-chlorophenoxy) -4-mefchoxymethyl-B-carboline-3-carboxylic acid isopropylamide? 6-( 2-chlorophenoxy) -4-methoxymethyl~B~carboline-3-carboxylic acid isopropylamide? -phenoxy-4-methoxymethyl-B-carboline-3-carboxylie acid isopropylamide.
Example 11 -PhenoxyrJjxmexhoxyme_thvl-B-carboline-3-ca£l3oxvlX£_acld 7.7 g of 5-phenoxy~4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester are heated with 70 ml of 2N sodium hydroxide solution until a clear solution has formed (2 hours). The mixture is then carefully acidified with 5N hydrochloric acid while hot and afterwards stirred for 15 minutes at room temperature. After suctioning off and drying over P2O5 and KOH at 80°C, 7.2 g (100% of theory) of 5«phenoxy-4-methoxymethyl~ B-carboline-3-carboxylic acid are obtained.
There are produced in analogous manners - (4-chlorophenoxy) -4-methoxymethyl-B-carboline~ 3-carboxylic acid? - (4-nitrophenoxy)-B-carboline-3-carboxylic acid; 6- phenoxy- B carboline-3-carboxylie acid; 6-phenoxy-4-methyl-β-carbo1ine-3-carboxylie acid; 6-(4-nitrophenoxy)-B-carboline-3-carboxylic acid; 6-(4-nitrophenoxy)-4-methyl-B-carboline-3-carboxylic acid; 6-( 4-chlorophenoxy) -4-methoxymethyl-B-carboline-3-carboxylic ac id; 6-(4-bromophenoxy)^-methoxymethyl-B-carboline-S-carboxylic acid; 6-(4-nitrophenoxy)-4-methoxymethyl~B«-carboline-3-carboxylic acid; 6-(2-nitrophenoxy)-4-methoxymethyl-B-c arboline-3-carboxy1ic acid; 6-( 2-methyl-4-nitrophsnoxy) -4-methoxymethyl~B~carboline-3~ carboxylic acid; 6-( 4-morpholinosulphamoylphenoxy ) -4-metho3cymethyl-B-carboline3-carboxylic acid; 6-(4-methylsulphonyIphenoxy)-4-methoxymethyl-B-carboline~3~ carboxylic ac id; 6-(4-diethylsulphamoylphenoxy)-4-methoxymethyl-B-carboline-3carboxylic acid; 6-(2-c hlorophenoxy) -4-methoxymethyl-B-carbo 1 ine-3-carboxylic ac id; 6-(4-cyanophenoxy)-4-methoxymethyl-B-carboline-3-carboxylic acid; 6-(4-fluorophenoxy)-fl-carboline-3-carboxylic acid; 6-( 2-chloro-4-nitrophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid; 6-(2,4-dichlorophenoxy)-4-methoxymethyl-B-carboline-3carboxylic acid; 6- ( 3-chlorophenoxy) -4~methoxymethyl~B-carboline~3-carboxylic acid; 6-(2-cyanophenoxy)-4~methoxyraethyl~B-carboline-3-carboxylic acid; 6-(2-cyano-3-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylie acid; 6-(2,3-dichlorophenoxy) ~>4-inethoxyniethyl~B-carboline~3carboxylic acid? 6-( 4-f luorophenoxy) "4"«iethoxymethyl-B-carboline-3-carboxylic acid.
Claims (8)
1. Phenoxy-substituted fl-carboline derivatives of the wherein X is an oxadiazolyl radical of the formula wherein R 2 is H, Chalky 1 or C 3 _7cycloalkyl, or Z is a COOR 3 group wherein R 3 is Cj^alkyl, or is CONHCx„ 3 alkyl, and R* is hydrogen, Ci. 6 alkyl or C,„ 5 alkoxyalkyl and R l is hydrogen, halogen, Chalky!, Cj^alkoxy, Ci. t alkanoyl, phenyl, C 2 . 5 a Iky lenedioxy , trifluoromethyl, cyano, nitro, G^alkoxycarbonyl, azido, SO 2 R% SO z NR 7 R 8 or NR ? R 10 , R a is Ci_ 6 alkyl? R 7 and R 8 are Ci^alkyl or together with the nitrogen atom form a saturated 5- or 6-membered heterocycle in which one or two CK 2 groups may be have been replaced by oxygen, sulphur or nitrogen, and R 9 and R 10 are each hydrogen, Ci_ 6 alkyl, C^alkanoyl or together with the nitrogen atom form a saturated 5or 6-membered heterocycle in which one or two CH 2 group* may have been replaced by oxygen, sulphur or nitrogen ? and there being from 1 to 3 substituent» R 1 , which may be identical or different,, and wherein X ia not COOC a SH s when ρ,ΐ—is 5- phenoxy and R* is methyl or when R*~ o 0-. ie 6- (4-sethoxyphene5£y| and, S* 1 is methoxywethyl.
2. 5« (4-Chlorophenoxy)-3-( 3-ethyl-l, 2,4-oxadiaxol-5-yl 1 -4methoxymethyl-B-carboline, 10 5-phenoxy-4-methyl-3-(3-ethyl-l,2,4-©xadiazol-5-yl)-βcarbol ine,, 5-(4-nitrophenoxy)-3-(3-ethyl-1,2,4-oxadiaxol-S-yl>-βcarboline, 5- ( 4-chlorophenoxy) -4-»ethyl-3- (3-ethyl-l, 2,4-oxadia2ol15 5-yl)-β-carboline, €-phenoxy-4-methyl-3-(3-ethyl-l,2,4-oxadiaxol-S-yl)-0carboline, 6- (4-chlorophen©xy> -4-methyl-3-( 3-ethyl-l, 2,4-oxadiazol5- yl) -β-carboline, 20 6-(4-aminophenoxy )-4 -jaethyl-3-< 3-ethyl-l, 2,4-oxadiaaol5~yl)~fi -carboline, 6 - (4 -chlor ©phenoxy ) -4 -methoxy®© t hy 1 - 3 - (3 -ethy 1 -1,2,4 oxadiazol-S-yl)-β-carboline, 6- (4 -chlorophenoxy) -4 -«ethoxymethyl - 3-(3 -eye 1 ©propy 1 25 1,2,4-oxadiaaol-S-yl)-S-earboline, 6-(4-sB©rpholin©sulphai®©ylphenoxy)-4-methoxyB»ethyl-3-(3cyclopropyl-I,2,4-©xadiasel-5-yl>-S-carboline, 6-(4-®ethylsulph©nylphenoxy)-4“®etfe©xfiaethyl-3“ (3-ethyl1,2,4-oxadiaz©l-5-yl>-B-earboline, 30 6-(2 -ehlorophenoxy | -4-methoxyaethyl -3-(3-ethy1-1,2,4oxadiazol-5-yl)-S-earboline, 6- (2, 4-dichlorophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2,4oxadiazol-5-yl)-β-carboline, 5- ( 4-nitrophenoxy) -4-methoxymethyl-β-carboline-3carboxylic acid ethyl ester, 5- (4-nitro-2-chlorophenoxy)-4-methoxymethyl-β-c arbo1ine3-carboxylic acid ethyl ester, 6- (4~nitrophenoxy) -4-methyl-fi-carboline-3-carboxylic acid ethyl ester, 6- ( 4-nitrophenoxy) -4-methoxymethyl-β-carboline-3carboxylic acid ethyl ester, 5- ( 4-aminophenoxy)-4-methoxymethyl~fl~carboline~3carboxylie acid ethyl ester, 5 -phenoxy- 4 -methoxymethyl -β-carboline- 3 -carboxyl ic acid ethyl ester, 5- ( 3-chlorophenoxy) -4-methoxymethyl-B-carboline-3~ carboxylic acid ethyl ester, 5- ( 2-chlorophenoxy) -4-methoxymet hy I-β-c arbo line-3carboxylic acid ethyl ester, 6- phenoxy-4-methoxymethyl-fl-carboline-3-carboxylic acid ethyl ester, 5- ( 4-chlorophenoxy) -4-methoxymethyl-B-carboline-3~ carboxylic acid ethyl ester, 5-(4-chlorophenoxy)-4-methyl-fl-carboline-3-carboxylic acid ethyl ester, 5- (2,4-dichlorophenoxy)-4-methoxymethyl-fi~carboline-3carboxylie acid ethyl ester, 6- ( 4-chlorophenoxy) -4-methoxymethyl-β-carboline-3carboxylie acid ethyl ester, 5·- (2-chlorophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4oxadiasol-5-yl)-β-carboline, 5-(3-chlorophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2, 4oxadiasol-5-yl)-β-carboline, 5- ( 2-chlorophenoxy) -4-methoxymethyl-β-carboline-3carboxylic acid isopropyl ester, 5- ( 2-nitrophenoxy)-4-methoxymethyl-B-carholine™3carboxylic acid isopropyl ester, 6-(2-cyano-3-chlorophenoxy)-4-methoxymethyl~fl-carboiin®~
3. -carboxylic acid isopropyl ester, 6-(2-cyanophenoxy)~4~methoxym©thyl~fi-carboline-3~ carboxylic acid isopropyl ester, 5- (4-acetylphenoxy) -4-methoxymethyl-3- ( 3-ethyl-l, 2,4oxadiazol-5-yl)-fl-carboline, 6- ( 3-me thyl phenoxy) - 4-methoxymethyl-β-carbol ine- 3carboxylie acid isopropyl ester, 6- ( 3-chlorophenoxy) -4-msthoxymethyl-fl-carboline-3carboxylic acid isopropyl ester, 6-(2,4-dichlorophenoxy)-4-methox'ymethyl-fl-carboline-3carboxylic acid ethyl ester, 5-phenoxy-4-methoxymethyl-β-c arboline-3-carboxy1ic ac id isopropyl ester, 5-( 4-chlorophenoxy) -4~methyl-B~carboline-3-carboxylic acid isopropyl ester, 5- ( 4-chlorophenoxy) -4-methoxymethyl-£-carboline-3carboxylie acid isopropyl ester, S _ ( 4 - chlorophenoxy) -4-methoxymethyl-β-carboline-3carboxylic acid isopropyl ester, 6- ( 4-f luorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropyl ester, 6-(3,4-dichlorophenoxy)-4-methoxymethyl-B~carboline-3carboxylic acid isopropyl ester, 5 -phenoxy- 4 -methoxymethyl -β-c arbol ine- 3 -c arboxy 1 ic ac id tert.-butyl ester, 6-phenoxy-4-methoxymethyl-B-carboline-3-carboxylic acid tert.-butyl ester, or 5- ( 4-chlorophenoxy) -4-methoxymethyl-B-carboline-3carboxylic acid isopropylamide, according to claim 1. A process for the preparation of the compounds of the general formula I according to claim 1, characterised in that a compound of the general formula II wherein R l and R* have the meanings given above, is reacted with a compound of the formula N0H R z -C \nh 2 wherein R 2 has the meaning given above, to form a compound of the general formula I wherein X is the radical wherein R 2 has the meaning given above, fo] a compound of the general formula III 'Ον EC ο i ·,>·* NOH Bfri. (III), 10 wherein R l and. R* have the meanings given above, is reacted with a carboxylic acid anhydride (R 2 CO) 2 O„ wherein R 2 has the meaning given above, to form a compound of the general formula I wherein X is the radical '‘Ν» -EC wherein R 2 has the meaning given above, c) a compound of the general formula IV wherein R 3 and R* have the meanings given above, is reacted with a compound of the formula 5 wherein Hal is halogen and R l has the meaning given above and R 1 ' is an electrophilic substituent, and optionally then a) a nitro group is reduced to the amino group end, if desired, the resulting amino group is deaminated or 10 replaced by halogen or aside, or β) when R 1 is halogen, is catalytically dehalogenated, or y) an ester group is transester if ied or hydrolysed and, if desired, the resulting carboxylic acid is 15 amidated.
4. ,, The use of the compounds according to claims 1 and 2 for the preparation, of medicaments.
5. Medicaments based on the compounds according to claims 1 and 2. - 41
6. A process for the preparation of a medicament by mixing a compound of the formula I prepared in accordance with claim 3 with a pharmaceutical carrier.
7. A compound substantially as hereinbefore described with 5 reference to the Examples.
8. A process substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853540654 DE3540654A1 (en) | 1985-11-13 | 1985-11-13 | PHENOXY-SUBSTITUTED SS-CARBOLINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE862996L IE862996L (en) | 1987-05-13 |
| IE61661B1 true IE61661B1 (en) | 1994-11-16 |
Family
ID=6286132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE299686A IE61661B1 (en) | 1985-11-13 | 1986-11-13 | Phenoxy-substituted beta-carboline derivatives, their production and their use as drugs |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4945090A (en) |
| EP (1) | EP0234173B1 (en) |
| JP (1) | JPH0699431B2 (en) |
| AT (1) | ATE90678T1 (en) |
| AU (1) | AU602497B2 (en) |
| CA (1) | CA1269377A (en) |
| DD (1) | DD254201A5 (en) |
| DE (2) | DE3540654A1 (en) |
| DK (1) | DK169702B1 (en) |
| ES (1) | ES2058064T3 (en) |
| FI (1) | FI84067C (en) |
| HU (1) | HU198046B (en) |
| IE (1) | IE61661B1 (en) |
| IL (1) | IL80618A (en) |
| NO (1) | NO163736C (en) |
| NZ (1) | NZ218244A (en) |
| PT (1) | PT83726B (en) |
| ZA (1) | ZA868631B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3540654A1 (en) * | 1985-11-13 | 1987-05-14 | Schering Ag | PHENOXY-SUBSTITUTED SS-CARBOLINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3540653A1 (en) * | 1985-11-13 | 1987-05-14 | Schering Ag | NEW 3-OXADIAZOLE AND 3-CARBONIC ACID SS-CARBOLINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3608089A1 (en) * | 1986-03-08 | 1987-09-10 | Schering Ag | HETEROARYL-OXY-SS-CARBOLINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3730667A1 (en) * | 1987-09-09 | 1989-03-23 | Schering Ag | Novel ss-carbolines |
| DE3729370C2 (en) * | 1987-08-31 | 1995-04-20 | Schering Ag | Process for the preparation of 4-alkoxyalkyl-beta-carbolines |
| DE4029389A1 (en) * | 1990-09-13 | 1992-03-26 | Schering Ag | METHOD FOR PRODUCING (BETA) CARBOLIN DERIVATIVES |
| DE4109342A1 (en) * | 1991-03-19 | 1992-09-24 | Schering Ag | SELECTIVE PHENYLATION OF 5-HYDROXY-SS-CARBOLINE DERIVATIVES |
| US5350750A (en) * | 1991-04-27 | 1994-09-27 | Schering Aktiengesellschaft | β-carboline-3-hydroxyalkylcarboxylic acid ester derivatives, process for their production and their use in pharmaceutical agents |
| DE4120109A1 (en) * | 1991-06-15 | 1992-12-17 | Schering Ag | 3-ARYL OR 3-HETARYL (BETA) CARBOLINES, THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS |
| US5543519A (en) * | 1991-06-15 | 1996-08-06 | Schering Aktiengesellschaft | 3-aryl or 3-hetaryl-β-carbolines, their production and use in pharmaceutical agents |
| HRP20150355T1 (en) * | 2009-01-12 | 2015-06-19 | Pfizer Limited | SULFONAMIDNI DERIVATI |
| US9145407B2 (en) | 2010-07-09 | 2015-09-29 | Pfizer Limited | Sulfonamide compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57123180A (en) | 1980-12-17 | 1982-07-31 | Schering Ag | 3-substituted beta-carboline, manufacture and psychotropic drug containing same |
| DE3322895A1 (en) | 1983-06-23 | 1985-01-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW SS CARBOLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT (S) |
| DE3504045A1 (en) * | 1985-02-04 | 1986-08-07 | Schering AG, 1000 Berlin und 4709 Bergkamen | METHOD FOR PRODUCING SS CARBOLINES BY DEHYDRATION |
| DE3540654A1 (en) * | 1985-11-13 | 1987-05-14 | Schering Ag | PHENOXY-SUBSTITUTED SS-CARBOLINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
-
1985
- 1985-11-13 DE DE19853540654 patent/DE3540654A1/en not_active Withdrawn
-
1986
- 1986-11-11 EP EP86730188A patent/EP0234173B1/en not_active Expired - Lifetime
- 1986-11-11 DE DE8686730188T patent/DE3688594D1/en not_active Expired - Lifetime
- 1986-11-11 NZ NZ218244A patent/NZ218244A/en unknown
- 1986-11-11 ES ES86730188T patent/ES2058064T3/en not_active Expired - Lifetime
- 1986-11-11 AT AT86730188T patent/ATE90678T1/en active
- 1986-11-12 PT PT83726A patent/PT83726B/en not_active IP Right Cessation
- 1986-11-12 HU HU864678A patent/HU198046B/en not_active IP Right Cessation
- 1986-11-12 CA CA000522771A patent/CA1269377A/en not_active Expired - Lifetime
- 1986-11-12 NO NO864517A patent/NO163736C/en unknown
- 1986-11-12 DD DD86296211A patent/DD254201A5/en not_active IP Right Cessation
- 1986-11-12 IL IL80618A patent/IL80618A/en not_active IP Right Cessation
- 1986-11-13 FI FI864619A patent/FI84067C/en not_active IP Right Cessation
- 1986-11-13 ZA ZA868631A patent/ZA868631B/en unknown
- 1986-11-13 JP JP61268799A patent/JPH0699431B2/en not_active Expired - Lifetime
- 1986-11-13 AU AU65170/86A patent/AU602497B2/en not_active Ceased
- 1986-11-13 DK DK543886A patent/DK169702B1/en not_active IP Right Cessation
- 1986-11-13 US US06/929,861 patent/US4945090A/en not_active Expired - Fee Related
- 1986-11-13 IE IE299686A patent/IE61661B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO163736B (en) | 1990-04-02 |
| ZA868631B (en) | 1987-06-24 |
| DD254201A5 (en) | 1988-02-17 |
| IL80618A0 (en) | 1987-02-27 |
| DE3540654A1 (en) | 1987-05-14 |
| EP0234173A2 (en) | 1987-09-02 |
| NO864517L (en) | 1987-05-14 |
| AU602497B2 (en) | 1990-10-18 |
| DK169702B1 (en) | 1995-01-16 |
| NO163736C (en) | 1990-07-11 |
| ATE90678T1 (en) | 1993-07-15 |
| DE3688594D1 (en) | 1993-07-22 |
| HUT43067A (en) | 1987-09-28 |
| PT83726B (en) | 1989-05-12 |
| IL80618A (en) | 1990-09-17 |
| DK543886D0 (en) | 1986-11-13 |
| AU6517086A (en) | 1987-05-21 |
| DK543886A (en) | 1987-05-14 |
| NZ218244A (en) | 1990-05-28 |
| EP0234173B1 (en) | 1993-06-16 |
| IE862996L (en) | 1987-05-13 |
| PT83726A (en) | 1986-12-01 |
| FI864619A7 (en) | 1987-05-14 |
| FI84067B (en) | 1991-06-28 |
| US4945090A (en) | 1990-07-31 |
| FI864619A0 (en) | 1986-11-13 |
| FI84067C (en) | 1991-10-10 |
| NO864517D0 (en) | 1986-11-12 |
| HU198046B (en) | 1989-07-28 |
| ES2058064T3 (en) | 1994-11-01 |
| JPS62167780A (en) | 1987-07-24 |
| JPH0699431B2 (en) | 1994-12-07 |
| CA1269377A (en) | 1990-05-22 |
| EP0234173A3 (en) | 1988-07-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |